Block polymer having functional groups at both ends

• US 5,929,177 A
• Filed: 02/05/1998
• Issued: 07/27/1999
• Est. Priority Date: 08/10/1995
• Status: Expired due to Term

• Current Assignee: Kazunori Kataoka
• Original Assignee: Kazunori Kataoka
• Inventors: Kataoka, Kazunori, Kato, Masao, Okano, Teruo, Nagasaki, Yukio
• Primary Examiner(s): Seidleck, James J.
• Assistant Examiner(s): Asinovsky, Olga
• Application Number:
  US09/011,329
• Time in Patent Office: 537 Days
• Field of Search: 525/408, 525/258, 424/78.17, 424/78.31, 424/78.37, 424/501, 528/409
• US Class Current: 525/408
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 63/676 in which at least one of the two components contains aliphatic unsaturation
• CPC Class Codes: C08G 63/912 derived from hydroxycarboxylic acids
• CPC Class Codes: C08G 65/2627 containing aromatic or arylaliphatic amine groups
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 85/00 General processes for preparing compounds provided for in this subclass
• CPC Class Codes: C08L 2666/18 Polyesters or polycarbonates according to C08L67/00 - C08L69/00; Derivatives thereof
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

The present invention provides a block polymer which has functional groups on its both ends, and which comprises hydrophilic/hydrophobic segments. As for the functional groups on its both ends, the block polymer has amino group, carboxyl group or mercapto group on α-terminal, and hydroxyl group, carboxyl group, aldehyde group or vinyl group on ω-terminal. Hydrophilic segment comprises polyethylene oxide, while hydrophobic segment is derived from lactide, lactone or (meth)acrylic acid ester. The block polymer of this invention forms a polymeric micelle which is usable as bio-compatible materials.

Claims

1. A block polymer which is represented by formula (I) below:

space="preserve" listing-type="equation">X--O.paren open-st.CH.sub.2 CH.sub.2 O.paren close-st..sub.m .paren open-st.Y.paren close-st..sub.n Z (I)

wherein X denotes an alkyl group having 1 to 10 carbon atoms which has one or two substituents selected from the group consisting of amino group blocked with amino-protecting group, carboxyl group blocked with carboxyl-protecting group and mercapto group blocked with mercapto-protecting group, or phenyl or phenyl-alkyl group which has the above-mentioned substituents on benzene ring;

Y denotes a group selected from the group consisting of the following recurring units ##STR122## wherein R¹ and R² independently denote hydrogen atom or alkyl group having 1 to 5 carbon atoms;

R³ denotes hydrogen atom or methyl group;

R⁴ denotes alkyl group having 1 to 5 carbon atoms which is substituted with hydroxyl group under circumstances;

q denotes an integer of 2-5;

Z denotes functional group selected from the group consisting of hydrogen atom, acryloyl group (CH₂ ═

CH--CO--), methacryloyl group (CH₂ ═

C(CH₃)--CO--), ##STR123## allyl group (CH₂ ═

CH--CH₂ --), ##STR124## mercapto group, alkyl group having amino group which is mono- or di-substituted under circumstances with alkyl group having 1 to 5 carbon atoms, alkyl group having carboxyl group or its ester group, alkyl group having aldehyde or its acetal group, and halogen atom; and

m and n independently denote an integer of 2-10,000.

2. The block polymer of claim 1 wherein X denotes an alkyl group having 1 to 10 carbon atoms which is substituted with amino group, carboxyl group or mercapto group which is not blocked with protecting group.

3. The block polymer of claim 1 wherein X denotes an alkyl group having 1 to 10 carbon atoms which is substituted with

amino group blocked with amino-protecting group selected from the group consisting of alkoxycarbonyl group having 1 to 5 carbon atoms;

benzylidene group whose benzene ring is substituted under circumstances with alkyl group having 1 to 3 carbon atoms or with halogen atom;

silyl group having three groups selected from the group consisting of alkyl group having 1 to 3 carbon atoms and phenyl group; and

cyano group, or carboxyl group blocked with carboxy-protecting group selected from the group consisting of alkoxy group having 1 to 5 carbon atoms;

benzyloxy group;

diphenylmethoxy group;

triphenylmethoxy group; and

cyano group, or mercapto group blocked with mercapto-protecting group selected from the group consisting of phenyl and benzyl.

4. The block polymer of claim 1 wherein X denotes an alkyl group having 1 to 10 carbon atoms which is substituted with amino group blocked with amino-protecting group which is benzylidene group, trimethylsilyl group or cyano group, or substituted with carboxyl group blocked with carboxy-protecting group which is tert.-butoxy group.

5. The block polymer of claim 1 wherein X denotes an alkyl group having 1 to 10 carbon atoms which is substituted with amino group or carboxyl group which is not blocked with protecting group.

6. The block polymer of claim 1 wherein Y denotes recurring units represented by the following formulae ##STR125## wherein alk denotes an alkyl group having 1 to 3 carbon atoms which is substituted, under circumstances, with hydroxyl group.

7. The block polymer of claim 1 wherein Z denotes hydrogen atom, acryloyl group or methacryloyl group.

9. A method to produce the block polymer of claim 1 which comprises the following steps:

(1) a step wherein the living block polymer represented by the following formula (II);

space="preserve" listing-type="equation">X.sub.a --O.paren open-st.CH.sub.2 CH.sub.2 O.paren close-st..sub.m .paren open-st.Y.paren close-st..sub.n-1 Y.sub.a M⊕

(II)

wherein Xa denotes an alkyl group having 1 to 10 carbon atoms which has one or two substituents selected from the group consisting of amino group blocked with amino-protecting group, carboxyl group blocked with carboxyl-protecting group and mercapto group blocked with mercapto-protecting group, or denotes a phenyl or phenyl-alkyl group which has the above-mentioned substituents on benzene ring;

Y and Ya each denote a group selected from the group consisting of groups represented by the following formulae ##STR127## wherein R¹ and R² independently denote hydrogen atom or alkyl group having 1 to 5 carbon atoms;

R³ denotes hydrogen atom or methyl group;

R⁴ denotes alkyl group having 1 to 5 carbon atoms which is substituted with hydroxyl group under circumstances; and

q denotes an integer of 2-5;

M.sup.⊕

denotes cation of alkaline metal selected from the group consisting of lithium, sodium, potassium and cesium; and

m and n independently denote an integer of 2-10,000.

is made to react in an inert solvent with an electrophile which is represented by the following formula ##STR128## wherein A denotes a group forming an active ester, D denotes chlorine, bromine or iodine, and Q denotes ##STR129## --CH═

CH₂, --COOC₂ H₅ or --CH₂ CH₂ (OCH₃)₂,

(2) a step to convert, if necessary, ##STR130## bound to Ya into mercapto group, amino group which is mono- or di-substituted under circumstances with an alkyl group having 1 to 5 carbon atoms, carboxyl group or halogen atom, with use of a corresponding nucleophilic reagent, and

(3) a step to eliminate, if necessary, the protecting group of Xa.

10. A polymeric micelle which comprises the block polymer of claim 1 as an effective ingredient.

8. A living block polymer represented by the following formula (II):

space="preserve" listing-type="equation">X.sub.a --O.paren open-st.CH.sub.2 CH.sub.2 O.paren close-st..sub.m .paren open-st.Y.paren close-st..sub.n-1 Y.sub.a M⊕

(II)

wherein Xa denotes an alkyl group having 1 to 10 carbon atoms which has one or two substituents selected from the group consisting of amino group blocked with amino-protecting group, carboxyl group blocked with carboxyl-protecting group and mercapto group blocked with mercapto-protecting group, or denotes a phenyl or phenyl-alkyl group which has the above-mentioned substituents on benzene ring;

Y and Ya each denote a group selected from the group consisting of groups represented by the following formulae ##STR126## wherein R¹ and R² independently denote hydrogen atom or alkyl group having 1 to 5 carbon atoms;

R³ denotes hydrogen atom or methyl group;

R⁴ denotes alkyl group having 1 to 5 carbon atoms which is substituted with hydroxyl group under circumstances; and

q denotes an integer of 2-5;

M.sup.⊕

denotes cation of alkaline metal selected from the group consisting of lithium, sodium, potassium and cesium; and

m and n independently denote an integer of 2-10,000.